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First published online January 26, 2005
doi: 10.1242/10.1242/jcs.01654

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Newcomers in the process of mitochondrial permeabilization

Department of Cell Biology, University of Geneva, 30 Quai Ernest-Ansermet, 1211 Geneva 4, Switzerland

View larger version (18K): [in a new window]   Fig. 1. Model for the mechanism of activation of Bak and Bax. In resting cells, Bak is a tail-anchored protein of the mitochondrial outer membrane (MOM) and associates with VDAC2, whereas Bax is loosely attached to mitochondria or sequestered in the cytosol, probably through interactions with retention factors (14-3-3 isoforms , , , ; humanin; Ku70; A- and B-crystallin; Hsp70-dj1 and Hsp70-dj2). Pro168 plays a crucial role both in preventing the inappropriate exposure of the N-terminal domain of Bax and in unleashing the C-terminal tail of Bax from its hydrophobic pocket as it occurs when Bax is activated (Schinzel et al., 2004b). After apoptosis induction, the conformations of Bak and Bax change, leading to exposure of their N-terminal domains and to oligomerization. Apoptogenic factors are then released from the mitochondrial intermembrane space. Several proteins have been suggested to participate in the activation of Bak and Bax, although the mechanisms through which they contribute remain unclear. In addition, some proteins promote apoptosis by inhibiting Bcl-2-like proteins.

View larger version (16K): [in a new window]   Fig. 2. (A) Following an apoptotic insult, BH3-only proteins are activated, at the transcriptional and/or the post-translational level, and neutralize their pro-survival counterparts. Activation of multidomain pro-apoptotic members of the Bcl-2 family proceeds through a largely unknown mechanism, although some BH3-only factors have been proposed to participate in the process. (B) Under resting conditions, pro-survival Bcl-2 family members sequester low levels of BH3-only proteins and prevent the full activation of multidomain Bax-like factors that would have undergone conformational rearrangements resulting in the exposure of their N-terminal domains.

View larger version (31K): [in a new window]   Fig. 3. Transcription-dependent and -independent mechanisms of p53-mediated apoptosis. In a cell-context-specific manner, p53 can activate the expression of pro-apoptotic genes and repress the transcription of pro-survival proteins (Ho and Benchimol, 2003). p53 can also translocate to the cytosol and associate with mitochondria. Direct effects of p53 on proteins of the Bcl-2 family have been proposed, as well as indirect effects through the upregulation of BH3-only proteins, p53AIP1 and ASC. In addition, p53 can promote the production of reactive oxygen species (ROS; Li et al., 1999) and activate caspases independently of mitochondria, perhaps through upregulation of PIDD (Lin et al., 2000), a protein involved in the activation of caspase-2 (Tinel and Tschopp, 2004).

View larger version (41K): [in a new window]   Fig. 4. When lipids are assimilated with solid structures, they can be divided into three groups (Israelachvili and Mitchell, 1975): flat lipids, which are roughly cylindrical; lipids with a positive curvature, which have a wider hydrophilic headgroup than the cross-sectional surface occupied by their acyl chains; and lipids with negative curvature, which have a smaller headgroup than the area of a cross-section of their hydrophobic part. Accumulation of lipids with positive curvature can create lipid pores in a lamellar bilayer, whereas lipids with negative curvature adopt a non-lamellar structure called hexagonal II phase. Both of these structures have been suggested to contribute to the permeabilization of the mitochondrial outer membrane that occurs during apoptosis. PC, phosphatidylcholine; PG, phosphatidylglycerol; PS, phosphatidylserine; PI, phosphatidylinositol; PE, phosphatidylethanolamine; DAG, diacylglycerol.